Stage- and Neuron Type Dependent Roles of the COP9 Signalosome in the Brain

The COP9 signalosome (CSN) is a nine-subunit protein complex that regulates protein degradation through deneddylation of cullin-based E3 ubiquitin ligases, with CSN5 acting as its catalytic subunit. Despite the importance of the ubiquitin-proteasome system in neuronal development and function, the contribution of CSN to brain development remains poorly understood. In this study, we investigated the consequences of CSN loss-of-function at distinct stages of neuronal development in mice. Using the Cre-loxP system, we conditionally deleted the CSN5 subunit in different neuronal populations. CSN5 ablation in proliferating neuroblasts using Nestin-Cre caused embryonic lethality, likely reflecting impaired cell division. Deletion in early postmitotic excitatory neurons using Nex-Cre resulted in lethality at postnatal day (PD) 1. In contrast, CSN5 deletion in inhibitory neurons using Dlx-Cre led to lethality between PD17 and PD21. Notably, CSN5 loss in mature excitatory neurons of the forebrain had no detectable effect on lifespan or gross brain morphology. Together, these findings reveal stage- and neuron type-dependent requirements for CSN during brain development, highlighting the distinct and context-specific functions of CSN functions in the developing brain.